1. Field of the Invention
The present invention describes novel phosphonate reagent compositions of the formula: ##STR3## wherein R and R'=C.sub.1 -C.sub.4 alkyl groups, or R, R'=(CH.sub.2).sub.n (n=2 or 3) or [CH.sub.2 C(CH.sub.3).sub.2 CH.sub.2 ].
Also described are novel methods for forming allenic C-15 phosphonate reagent compositions (4) from ethynyl-pseudoionone (3) (systematically named as 3,7,11-trimethyl-4,6,10-dodecatrien-1-yn-3-ol).
Allenic reagent compositions (4) can be partially hydrogenated to form allylic C-15 phosphonate compounds of the formula: ##STR4## wherein R and R'=C.sub.1 -C.sub.4 alkyl groups.
Phosphonate compounds (5) can be employed as precursors to a variety of biologically-active materials, including lycopene (7). Accordingly, the invention also describes a four-step route for the conversion of pseudoionone (2) to lycopene (7).
2. Description of Related Art
(a) Prior Art Processes for Preparation of Lycopene and Utility of Lycopene
There are approximately 600 naturally occurring carotenoids, but only six of these have so far been produced industrially. Insofar as applicants are aware, the only companies that manufacture synthetic "nature-identical" carotenoids at the present time are Roche (since 1954) and BASF (since 1960). Sales of such compounds are growing rapidly and in 1995 surpassed 500 million U.S. dollars. [Reference: "Carotenoids; Volume 2: Synthesis," edited by G. Britton, et al. (Birkhauser Verlag, Basel, 1996), page 259]. This reference indicates that the symmetrical acyclic C.sub.40 -carotenoid lycopene (7), which is the red coloring matter of tomatoes, has potential commercial value. Indeed, chemists at Roche have recently developed an industrially feasible synthesis of lycopene, although it requires the use of a very costly raw material (triphenylphosphine). See: K. Meyer, et al., Helv. Chim. Acta 1992, 75, 1848.
Compared to .beta.-carotene, lycopene exhibits higher radical scavenging properties, which makes it an interesting candidate for antioxidant activity studies in humans [H. Gerster, J. Am. Coll. Nutr. 1997, 16, 109]. Levy and coworkers [Nutr. Cancer 1995, 24, 257] showed the inhibitory effect of lycopene on the growth of human endometrial, mammary, and lung cancer cells; and it has been verified that a lycopene-rich diet decreases the risk of prostate cancer [E. Giovannucci, et al., J. Natl. Cancer Inst. 1995, 87, 1767]. Indeed, it is now thought that lycopene is important in giving protection against a variety of serious disorders including cancer, heart disease, and degenerative eye diseases. For example, lycopene is known to be an antitumor agent against brain tumors [Chem. Abstracts 1990, 112 91375w]. Also interesting is the report in a recent Japanese patent [Chem. Abstracts 1991, 115, 214528v] that a topical solution of lycopene controls acne and also markedly promotes hair growth in mice.
The first synthesis of lycopene (7) was reported in 1950 [P. Karrer, et al., Helv. Chim. Acta 1950, 33, 1349], but suffered from a low overall yield (0.1%) starting with pseudoionone (2). Subsequent syntheses of lycopene starting with pseudoionone proceeded in overall yields as high as 20% [e.g., B. C. L. Weedon, et al., J. Chem. Soc. 1965, 2019]. However, all such syntheses required too many steps and/or the use of costly raw materials (e.g., triphenylphosphine). Other syntheses of lycopene can be found in: O. Isler, et al., Helv. Chim. Acta 1956, 39, 463; K. Bernhard and H. Mayer, Pure & Appl. Chem. 1991, 63, 35; and Chem. Abstracts 1991, 114, 82198e.
(b) Prior Art Processes for Forming Pseudoionone
A preliminary step in a preferred method for preparing the compounds of the present invention involves the preparation of pseudoionone (2) [IUPAC name: 6,10-dimethyl-undeca-3,5,9-trien-2-one]. This specialty chemical can be prepared by a crossed-aldol condensation of citral (1) [IUPAC name: 3,7-dimethylocta-2,6-dienal] with acetone: ##STR5##
Alternatively, pseudoionone (2) can be prepared by the following four-step route starting with isoprene (as disclosed in Babler et al., U.S. patent application Ser. No. 09/161,983, filed on Sep. 19, 1998, the disclosure of which is hereby incorporated by reference): ##STR6## (c) Prior Art Processes for Forming 3.degree. Propargylic Alcohols.
The first step in a preferred method for preparing the compounds of the present invention involves the addition of acetylide to pseudoionone (2) to form a 3.degree. propargylic alcohol (3) in high yield: ##STR7## See O. Isler, et al., Helv. Chim. Acta 1961, 44, 985. (d) Prior Art Processes for Converting 3.degree. Propargylic and Allylic Alcohols to Allenic and Allylic Phosphonates
The second step in the preparation of phosphonate reagent compositions (4) is a novel process wherein ethynyl-pseudoionone (3) (systematically named as 3,7,11-trimethyl-4,6,10-dodecatrien-1-yn-3-ol) is reacted with a dialkyl chlorophosphite. Processes wherein structurally-simple 3.degree. propargylic alcohols have been converted to allenic phosphonates have been described: ##STR8## For examples of the above reaction, see: H. J. Altenbach and R. Korff, Tetrahedron Lett., 1981, 22, 5175 and U.S. Pat. No. 3,197,497.
In a similar process, 3.degree. allylic alcohols have been converted into allylic phosphonates: ##STR9##
However, ethynyl-pseudoionone (3) could have undergone dehydration (yielding 3,7,11-trimethyl-3,5,7,10-dodecatetraen-1-yne) when treated with ClP(OCH.sub.2 CH.sub.3).sub.2 in the presence of a tertiary amine, instead of being converted into the novel C-15 allenic phosphonate (4). Indeed, the closely-related ethynyl-.beta.-ionol has been reported to undergo dehydration when treated (0.degree. C. to room temperature) with phosphorous oxychloride and a non-nucleophilic base (e.g., a tertiary amine such as pyridine or triethylamine): ##STR10## See M. J. Szwedo, Jr., STUDIES DIRECTED TOWARDS THE TOTAL SYNTHESIS OF RETINOIDS, Ph.D. Dissertation, Loyola University of Chicago, 1983, pages 24 & 57-59.